The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK and NIMH, is the synthesis and evaluation of analogs of GBR12909 as putative cocaine antagonists or cocaine substitution-type medications. We have synthesized and evaluated over 100 novel GBR analogs, including the first chiral ""GBR"" derivatives which are potent and enantioselective inhibitors of dopamine reuptake. Related studies in Rhesus monkeys showed that daily administration of GBR12909 suppresses cocaine self-administration in without the development of tolerance, supporting its potential use in the treatment of cocaine addiction. Other studies showed that GBR12909 blocks the increase in extracellular DA produced by intravenous cocaine in the nucleus accumbens of behaviorally active rats. Another component involves a search for novel cocaine binding sites in the CNS. This project has identified multiple and novel binding sites for the high affinity cocaine analog, [125I]RTI-55. Another component of this project addresses the role of classical conditioning in cocaine-induced behavioral sensitization. These studies demonstrated that associative learning mechanisms are involved in the acquisition of context-specific behavioral sensitization to cocaine. Studies with genetically inbred strains of mice showed that the occurrence of sensitization is not correlated with either the potency or efficacy of cocaine as a motoric stimulant. Human studies failed to demonstrate cocaine-sensitization with a one day training paradigm (DIR-174). Various studies examining the endocrine effects of cocaine in humans and rats are underway. Open-label studies with phentermine and fenfluramine showed that these medications suppress cocaine craving in addicts seeking treatment, may facilitate abstinence from nicotine, and may be a useful treatment for attention deficit disorder. Clinical research protocols are in preparation to determine the efficacy of fenfluramine and phentermine as treatments for alcohol and cocaine addiction.